The Toll-like Receptor (TLR) superfamily plays a central role in the recognition of invading pathogens and the initiation of an immune response. Each TLR recognises a distinct pathogen-associated molecular pattern (PAMP) leading to the activation of a signalling cascade, which in turn activates the transcription factor NF-KB and also the mitogen-activated protein kinases (MAPKs), p38, c-jun, N terminal kinase (JNK) and p42/44. Toll-like Receptor 4 (TLR-4, TLR4) also activates a further pathway which culminates in the activation of the transcription factor IFN-regulated factor-3 (IRF3), which binds to the interferon-sensitive response element (ISRE), inducing a subset of genes including interferon beta. The TLRs are members of a larger superfamily, called the interleukin-1 receptor (IL-1R)/TLR superfamily, that also contains the IL-1R1 subgroup and the TIR domain-containing adaptor subgroup. All three subgroups possess a cytoplasmic Toll/IL-1 receptor (TIR) domain, which is essential for signalling. The TLRs possess extracellular leucine rich repeats, while the IL-1R1 subgroup have extracellular immunoglobin domains.
The inventors have surprisingly identified that Toll-like Receptor 14, a protein characterised as comprising the amino acid sequence of SEQ ID NO:1 in the human form, or the amino acid sequence of SEQ ID NO:3 in the murine form, acts as a co-receptor with the Toll-like Receptor, Toll-like Receptor 4 (TLR4). The inventors have shown that signalling mediated by TLR4 following the activation of TLR4 with endotoxin (a defined pathogen-associated molecular pattern (PAMP) of TLR4) is suppressed in cells where there is an inhibition of TLR14 expression, for example as a result of siRNA mediated TLR14 knockdown.
TLR4 has a recognised importance in relation to endotoxin-mediated signalling. Endotoxin-mediated signalling through TLR4 can result in conditions such as septicaemia and sepsis. It is therefore desirable to identify compounds and agents which can modulate the function of TLR4, and in particular which suppress TLR4 activation and signalling in response to endotoxins, such as lipopolysaccharide (LPS).